DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal recessive osteopetrosis 7 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAutosomal recessive osteopetrosis 7 maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for autosomal recessive osteopetrosis 7 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
What the evidence adds up to
Autosomal recessive osteopetrosis 7 is caused by homozygous mutation in the OSTM1 gene. OSTM1 mutations account for approximately 5% of instances of autosomal recessive osteopetrosis. This form leads to a highly debilitating disease in infancy and death within the first few years of life. The OSTM1 protein trafficking function is essential for osteoclast maturation, and OSTM1 plays a primary and direct role in the central nervous system. Among the autosomal recessive osteopetroses, OSTM1 is the most severe form in both mice and humans.
The autosomal recessive osteopetroses are rare genetic skeletal disorders with an estimated frequency of 1:250,000 worldwide. Manifestations are diverse and include high bone density, hepatosplenomegaly, visual and hearing loss, and anaemia. Genetic heterogeneity in clinical presentation has been discussed. Whole exome sequencing has confirmed TCIRG1 as the most frequently mutated gene in autosomal recessive osteopetrosis, and has identified mutations in other known genes and in genes very rarely associated with the disease, namely FERMT3 and USB1. Deep intronic mutations in TCIRG1 and synonymous changes in TCIRG1 and CLCN7 have been demonstrated to be causative.
In one cohort, molecular diagnosis was performed for 4 patients with autosomal dominant osteopetrosis who carried mutations in LRP5 and CLCN7. Whole exome sequencing also helped in differential diagnosis in a patient found to bear a mutation in FAM20C, known to cause Raine syndrome. The potential limitations of whole exome sequencing have been highlighted, specifically regarding deep intronic mutations and synonymous changes, and the importance of complementing sequencing with transcript-level analysis and functional validation has been underlined.
What is still missing for autosomal recessive osteopetrosis 7 specifically is any clinical trial testing a drug, any patient stratification beyond the genetic diagnosis, and any funding directed toward treatment development for this OSTM1 form. The disease is extremely rare, and no therapy has been reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Bone · 2022 · 9 citations · open access
OSTM1 pleiotropic roles from osteopetrosis to neurodegeneration
AbstractAutosomal recessive osteopetroses (ARO) are rare genetic skeletal disorders of high clinical and molecular heterogeneity with an estimated frequency of 1:250,000 worldwide. The manifestations are diverse and although individually rare, the various forms contribute to the prevalence of a significant number of affected individuals with considerable morbidity and mortality. Among the ARO classification, the most severe form is the autosomal recessive-5 (OPTB5) osteopetrosis (OMIM 259720 ) that results from homozygous mutation in the OSTM1 gene (607649). OSTM1 mutations account for approximately 5 % of instances of autosomal recessive osteopetrosis and lead to a highly debilitating form of the disease in infancy and death within the first few years of life (Sobacchi et al., 2013) [1] . • OSTM1 is the more severe form of ARO in mice and humans. • The OSTM1 protein trafficking function is essential for osteoclast maturation. • OSTM1 plays a primary and direct role in the central nervous system.
AbstractOsteopetrosis is a disorder characterized by high bone density, hepatosplenomegaly, visual and hearing loss, and anemia. Pycnodysostosis presents with short stature, acroosteolysis, and dense bones. We, hereby, present here a family with autosomal dominant osteopetrosis and also children with recessive osteopetrosis and pycnodysostosis. The molecular confirmation was done in 3 cases. Genetic heterogeneity in clinical presentation is discussed here. Further studies will help in identifying epigenetic alterations and population-specific variants and also developing targeted therapies.
Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) · 2018 · 0 citations · open access
NEW INSIGHTS IN BONE BIOLOGY FROM EXOME SEQUENCING OF RARE SKELETAL DISEASES
AbstractWhole exome sequencing (WES) is a powerful tool to identify new molecules involved in skeletal homeostasis. In particular we used WES to establish the molecular diagnosis of two particular skeletal diseases: osteopetrosis and the acrofrontofacionasal dysostosis 1 (AFFND1). The osteopetroses are a group of rare bone diseases characterized by increased bone density due to the failure in bone resorption. Due to their genetic heterogeneity, WES represents a valuable strategy to identify the genetic defect. We analyzed osteopetrotic patients with autosomal dominant osteopetrosis (ADO) and autosomal recessive osteopetrosis (ARO), which is the most severe form. In our cohort we performed molecular diagnosis of 4 ADOI or ADOII patients that carried mutations in the LRP5 and CLCN7 genes, respectively. The analysis of ARO patients confirmed TCIRG1 as the most frequently mutated gene, identified mutations in the other known ARO genes and in genes very rarely associated with osteopetrosis, namely FERMT3 and USB1. Of note, we demonstrated the causative role of four deep intronic mutations in TCIRG1 gene and two different synonymous changes in the TCIRG1 and CLCN7 genes in the pathogenesis of the disease. In addition, WES helped in the differential diagnosis in a patient who was found to bear a mutation in the FAM20C gene, known to cause Raine syndrome. Regarding AFFND1, this is an extremely rare syndrome, comprising facial and skeletal abnormalities, short stature and intellectual disability. WES found a novel truncating mutation in the neuroblastoma-amplified sequence (NBAS) gene in two Indian patients (c.6237-3C>G). This mutation impaired NBAS functions in HEK293T cells overexpressing the truncated NBAS protein. Furthermore, we demonstrated that NBAS expression in mouse embryos was compatible with a role in bone and brain development and that the depletion of endogenous z-nbas in fish embryos resulted in defective morphogenesis of chondrogenic cranial skeletal elements. Overall, we provided evidence supporting the hypothesis of a causative role of the mutated NBAS gene in the pathogenesis of AFFND1. In conclusion, we effectively exploited WES in the genetic diagnosis of rare skeletal diseases. We also highlighted potential limitations of this approach, specifically with respect to deep intronic mutations and synonymous changes, and underlined the importance to complement WES with analysis at the transcript level and functional validation, when possible.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
